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Published by support, 2018-04-05 01:09:42

PD-1/PD-L1 Checkpoint in Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report


Keywords: Breast Implant,Anaplastic Large Cell Lymphoma

Authored by

Antonella Bianchi

Unit of Pathology, University Hospital Campus Bio-Medico,

Published Date
March 16, 2018

Published in the Journal of

Biomedical Journal of Scientific & Technical Research

Biomedical Research Network+, LLC
600 Third Avenue, 2nd floor,
New York - 10016,

DOI: 10.26717/BJSTR.2018.03.000865 Volume 3- Issue 2: 2018
Antonella Bianchi. Biomed J Sci & Tech Res
ISSN: 2574-1241
Case Report
Open Access

PD-1/PD-L1 Checkpoint in Breast Implant-Associated
Anaplastic Large Cell Lymphoma: A Case Report

Antonella Bianchi1*, Simona Ferrari1, Gabriella Gullotta1, Antonella Grasso2 and Ombretta Annibali3

1Unit of Pathology, University Hospital Campus Bio-Medico, Italy
2Breast Care Unit, University Hospital Campus Bio-Medico, Italy
3Unit of Hematology, Stem Cell Transplantation, University Hospital Campus Bio-Medico, Italy
Received: March 05, 2018; Published: March 16, 2018
*Corresponding author: Antonella Bianchi, Unit of Pathology, University Hospital Campus Bio-Medico, Via Alvaro del Portillo, 200, Rome, Italy,
Tel: ; Email:


Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare form of malignancy that arises around mammary implants in
patients undergoing prosthetic surgery. It has been included as a provisional entity in the revised WHO classification of lymphoid malignancy.
The PD-1/PD-L1 axis is one of the major mechanisms of immune escaping exerted by several cancer types in which up-regulation of PD-L1 is
observed. We report the presence of PD-1/PD-L1 checkpoint in a case of BI-ALCL of a 67 year old woman, whom previously had undergone
mastectomy and reconstruction for breast carcinoma.

Keywords: PD-1/PD-L1; BI-ALCL; Lymphomas; Lymphoprolipherative Diseases

Abbreviations: PD-1: Programmed Death-1; PD-L1: Programmed Death-Ligand 1; BI-ALCL: Breast Implant-Associated Anaplastic Large Cell
Lymphoma; ALK: Anaplastic Lymphoma Kinase; TCR: T-Cell Receptor; CHL: Classical Hodgkin’s Lymphoma; PTCL: Peripheral T-cell Lymphoma;
FFPE: Fixed Formalin Paraffin Embedded

Introduction clinical course as compared to those lacking ALK gene lesions (ALK-
ALCL) [5].
Primary breast lymphomas are rare and account for
approximately 0.04 to 0.5% of all breast cancers, with an estimated BI-ALCL has an ALK-negative phenotype and, similarly to
incidence of 1 case per 500.000 to 3 million women with implants primary cutaneous ALCL (cALCL) [6], cases confined to the peri-
[1]. The majority of these non-Hodgkin’s lymphomas that affect the implant breast seroma fluid without invasion of the fibrous capsule
breast derive from B-lymphocytes and less than 10% are of T-cell have shown an excellent prognosis [7]. The PD-1/PD-L1 axis is
origin [2]. In recent years, a distinct subset of T-cell lymphomas, one of the major mechanisms of immune escaping exerted by
so-called breast implant-associated anaplastic large cell lymphoma several cancer types in which up-regulation of PD-L1 is observed.
(BI-ALCL) has been described in women with breast implants. It was Programmed death-1 (PD-1) receptors are expressed on activated
first described in 1997 and included in 2017 as a new provisional T cells, and function to limit T-cell-mediated immune responses.
entity in the revised WHO classification of lymphoid malignancy PD-1 ligands, PD-L1 (B7-H1 or CD274) and PD-L2 (B7H3 or
within the group of the anaplastic large cell lymphoma (ALCL) [3]. CD273), are physiologically expressed respectively by a subset of
ALCL is a specific subtype of peripheral T-cell lymphoma (PTCL) cells of the hematopoietic lineage (B cells, T cells and macrophages)
in which the different sub-entities, though sharing the presence of and by antigen-presenting cells and epithelial tissues. They can be
CD30-positive large atypical lymphocytes, substantially differ for up-regulated in certain solid tumors and lymphomas. PD-L1 upon
clinical presentation (i.e. systemic, primary cutaneous, associated binding to PD-1 receptors, leads to the reduction of T-cell receptor
with breast implants) and behavior [4]. Among systemic ALCLs (TCR) signaling, which is essential in maintaining immune tolerance
(sALCL), those harboring translocations of anaplastic lymphoma and balanced responses to eliminate pathogens and tumor cells.
kinase gene (ALK) (ALK+ ALCL) have shown a more favourable

Cite this article: Antonella B, Simona F, Gabriella G, Antonella G, Ombretta A. PD-1/PD-L1 Checkpoint in Breast Implant-Associated 3/4
Anaplastic Large Cell Lymphoma: A Case Report. Biomed J Sci &Tech Res 3(2)- 2018. BJSTR.MS.ID.000865. DOI: 10.26717/BJSTR.2018.03.000865

Antonella Bianchi. Biomed J Sci & Tech Res Volume 3- Issue 2: 2018

There are Two Mechanisms of Expression of Immune Checkpoint all suggesting a multicentric cancer. Mammograms confirm the
Ligands on Tumors Cells presence of three lesions associated to microcalcifications. The
subsequent cytology reported the diagnosis of carcinoma. The
a) Constitutive expression of PD-L1 by tumors cells patient underwent mastectomy and axillary dissection plus
because of genetic alterations to the PD-L1 and PD-L2 locus of reconstruction by tissue expander. Histopathology reported
chromosome 9p24.1 (gains, amplifications or fusions); multiple high grade ductal infiltrating carcinoma associated to
high grade ductal carcinoma in situ and microscopic aspects of
b) Activation of signaling pathways, independent of lymphovascular invasion; on immunohistochemistry, tumor cells
inflammatory signals (intrinsic immune resistance) or through expressed estrogen and progesterone receptors, Ki67 15%, HER2
an induced response to inflammatory signals produced by negative (Luminal A-like subtype). All 16 lymph nodes removed
an active anti-tumor immune response (adaptive immune were negative. She received ormonotherapy with an Aromatase
resistance). inhibitor until February 2015.

The disruption of PD-1/PD-L1 interaction using antibodies In 2011 the patient underwent the second stage reconstruction
directed against PD-1 (Nivolumab and Pembrolizumab) or PD- with silicone implant placement and contra lateral symmetrisation.
L1 (Atezolizumab) restores the T cell capability to exert cytolytic The follow up was negative until February 2017 when two residual
functions directed to neoplastic cells [8]. auxiliary lymph node were revealed by ultrasound examination
associated with the presence of peri-prosthetic effusion, found
Furthermore, the assessment of PD-L1 expression through in a control CT scan. Whole body positron emission tomography-
immunohistochemical staining is considered as the best biomarker computed tomography (PET/CT) scan with Huorodeoxyglucose
that allows better selection of patients who are likely to respond (FDG) radiotracer revealed increased FDG uptake only in the
to targeted immunotherapy, to improve treatment efficacy and axillary region with a maximum SUV of 6.4 and in the external
to manage cost of therapies [9]. Although classical Hodgkin’s quadrants of the right breast.
lymphoma (cHL) is considered the prototype of lymphoid
malignancies susceptible to blockade of PD-1/PD-L1 checkpoint For this reason, the patient underwent first diagnostic
[10] the success of checkpoint blockade therapy in the treatment dissection of palpable lymph nodes and then to lymphadenectomy
of different solid tumors has encouraged the research for similar and capsulectomy (Figure 1) with extraction of silicone implant
results in the wide spectrum of lymphoproliferative diseases [9,11- and drainage of peri-prosthetic fluid. Histopathologically, clusters
13]. Our work provides the first evidence of the expression of PD- of lymphoma cells were present in the peri-prosthetic fluid and
L1 in BI-ALCL among the broad variety of lymphoid malignancies. in the fibrous capsule surrounding the implant, but not beyond
it. The lymph node was characterized by intrasinusal infiltrate
Case Presentation of highly pleomorphic cells with horseshoe-shaped and simil-
Reed-Sternberg nuclei, with prominent nucleoli. The tumour cells
The patient was a 67-year-old woman who noticed in 2010 were immunohistochemically positive for CD30, CD15, CD4, CD5,
a lump in the upper outer quadrant of her right breast. Clinical Perforin, Granzyme, MUM1/IRF4 and demonstrated negative
examination revealed a thick, movable 3×3 cm nodule. Sonographic immunostaining for ALK, LMP1, pan-B-cell and epithelial markers.
examination revealed a rounded hypoechoic lump 3 cm in diameter Others T-cell markers were down regulated.
with irregular contour with increased perfusion; in the upper
quadrants of the same breast it showed others two lesions with the
same characteristics, 13.6 mm and 8 mm in diameter respectively,

Figure 1: The excised BI-ALCL capsular tissue. 4/4

Biomedical Journal of
Scientific & Technical Research (BJSTR)

Antonella Bianchi. Biomed J Sci & Tech Res Volume 3- Issue 2: 2018

Figure 2: The neoplastic cells exhibiting strong membranous staining immunoreactivity for PD-L1 (22C3 DAKO). (200 X).

Almost all tumor cells (± 90%) showed expression for PD- surrounding the implant and not of the breast parenchyma. Silicone
L1 [22C3 DAKO, Agilent Technologies] with specific, strong, and might be immunogenic stimulating a chronic inflammation and, such
fully membranous staining pattern (Figure 2) [11,13]. PD-L1 as Helicobacter pylori infection in gastric extra nodal marginal zone
expression was also evaluated in non-neoplastic cells. A weak lymphoma, could be associated with development of lymphomas.
membranous partial stain was observed in ± 20% of adjacent Moreover, ALCL originates from activated mature cytotoxic T cells
nodal histiocytes [14]. Immunohistochemistry was performed [15]. The overexpression of PD-L1 has never been described before
with the automated device Dako Omnis (Agilent Technologies’) in BI-ALCL between the wide spectrums of lymphoproliferative
to ensure repeatability and reproducibility. Appropriate positive diseases. It could be related to the deregulation of genes involved in
and negative controls were routinely included for intra-laboratory the inflammatory reaction, well known in BI-ALCL, supporting an
optimization of the tests. The staging at the time of diagnosis, immune pathogenetic mechanism of lymphomagenesis [16].
according to Clemens et al., was T3, N1, M0 [7]. Bone marrow
biopsy showed no evidence of lymphoma involvement. As patients Besides these intriguing aspects, since targeted therapy has
with positive regional lymphnode involvement at diagnosis have a recently shown encouraging results, as, for example, Brentuximab-
higher rate of recurrence, CHOP systemic treatment has been the Vedotin (BV) for cases overexpressing CD30 antigen, also PD-L1
therapeutic option chosen after capsulectomy. The patient, still assessment by immunohistochemistry could be proposed as a
under treatment when publishing, will continue close surveillance predictive assay for selecting patients who do not have responded to
following completion of chemotherapy. conventional chemotherapy, potentially treatable with checkpoint
blockade therapies [17]. Due to this essential role as biomarker, from
Discussion a technical point of view, all pre-analytical (tissue fixation, handling,
processing and treatment of histological sections) and analytical
BI-ALCL is considered a disease of the fibrous capsule issues (immunohistochemical visualization system, commercial

Biomedical Journal of 5/4
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Antonella Bianchi. Biomed J Sci & Tech Res Volume 3- Issue 2: 2018

staining platform, chromogen, primary antibody, pre-treatment) 7. Clemens MW (2016) Complete Surgical Excision Is Essential for the
must be carefully considered in the pathology laboratory when Management of Patients With Breast Implant-Associated Anaplastic
immunohistochemical tests are performed on FFPE (fixed formalin Large-Cell Lymphoma. J Clin Oncol 34(2): 160-168.
paraffin embedded) tissue. Moreover, morphologic evaluation is
fundamental to correctly apply a scoring algorithm in an exhaustive 8. Bianchi A (2017) PD-1/PD-L1 checkpoint in lymphoproliferative
pathologic report. malignancies: focus on critical points for tissue assessment. ARC
Journal of Haematology 2(2): 1-6.
9. Gravelle P (2017) Mechanisms of PD-1/PD-L1 expression and
In conclusion, however further studies would be necessary for prognostic relevance in non-Hodgkin lymphoma: a summary of
the validation of reporting criteria, pathologists and haematologists immunohistochemical studies. Oncotarget 8(27): 44960-44975.
should continue to collaborate for the optimization of the PD-L1
immunohistochemical assays for the patients affected by different 10. Ansell SM (2015) PD-1 blockade with nivolumab in relapsed or
subtypes of lymphomas and considered for immunotherapy. refractory Hodgkin’s lymphoma. N Engl J Med 372(4): 311-319.

Acknowledgement 11. Menter T (2016) Evaluation of the diagnostic and prognostic value
of PDL1 expression in Hodgkin and B-cell lymphomas. Hum Pathol
The authors are deeply grateful to Alessandra Innocenzi for 54: 17-24.
excellent technical assistance.
12. Bledsoe JR (2016) The immunophenotypic spectrum of primary
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Cite this article: Antonella B, Simona F, Gabriella G, Antonella
G, Ombretta A. PD-1/PD-L1 Checkpoint in Breast Implant-
Associated Anaplastic Large Cell Lymphoma: A Case Report.
Biomed J Sci &Tech Res 3(2)- 2018. BJSTR.MS.ID.000865.
DOI: 10.26717/BJSTR.2018.03.000865

Authored by

Antonella Bianchi

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